This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease has been viewed as a disease primarily affecting motor neurons. We now know that cognitive dysfunction, with abnormalities in thinking and memory, occur in some patients suggesting that ALS may not be limited to motor neurons. Several techniques in brain scanning, particularly MRI, allow for examination of changes in the structure and function of the brain. It is not known whether ALS patients with normal cognitive function differ from those with cognitive dysfunction with respect to structural and/or functional abnormalities on brain MRI. The goals of this study are to examine cognitive function in ALS in parallel with findings on MRI over 12 months to assess changes over time and to correlate them with other commonly used clinical measures of disease severity, such as ALS function and ALS Health State. Hypotheses Hypothesis #1: MRI abnormalities will be greater in ALS patients with cognitive dysfunction than those without, after controlling for disease severity. Hypothesis #2: ALS patients with cognitive dysfunction will demonstrate brain activation patterns on functional MRI (fMRI) that are different from those without cognitive dysfunction, after controlling for disease severity. Specific Aims To test these hypotheses we propose to undertake the following experiments: 1.) To undertake formal neurocognitive testing and MRI scans in ALS patients and healthy controls for comparison between groups and correlation of cognitive data with MRI data in ALS patients. 2.) To perform serial MRI studies and fMRI in ALS patients at 4-month intervals to determine changes over time and permit correlations with cognitive abnormalities and clinical measures of disease severity. Procedures ALS patients and healthy normals (spouses or regulars) will undergo cognitive testing, MRI brain scans, and specialized cognitive testing while in the MRI machine. This will permit an analysis of the structure of the brain, and how it is activated during specialized testing when subjects perform a task of enumerating words starting with specific letters. Normals will be tested once, and ALS patients will be tested every 3-months for a year. Statistical tests will permit comparisons of differences between ALS patients and normals. Significance These studies will not only enhance our understanding of the cognitive changes in ALS and its relation to other neurological illnesses associated with dementia, but also provide preliminary data for an in-depth examination of cognitive dysfunction and approaches to its possible treatment in the future.